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mtARS: Mitochondrial Aminoacyl-tRNA Synthetase Disorders

Nov 15, 2024

  • General
  • Genetics
  • Symptoms
  • Resources

General Info for mtARS: Mitochondrial Aminoacyl-tRNA Synthetase Disorders

Overview

Mitochondrial ARS (Aminoacyl-tRNA Synthetase) Disorders (mtARS) are a group of rare genetic disorders. The disorders are caused by mutations in the aminoacyl-tRNA synthetases (ARS) genes, which are responsible for the production of enzymes essential for mitochondrial protein synthesis.

Genetics

Affected Genes

AARS2, CARS2, DARS2, EARS2, FARS2, GARS, HARS2, IARS2, KARS, LARS2, MARS2, NARS2, PARS2, QARS, RARS2, SARS2, TARS2, VARS2, WARS2, YARS2

Inheritance Type(s)
  • Autosomal recessive
Cause and Genetics

Mitochondrial ARS Disorders are all genetic conditions, meaning they are passed down in a family. To be affected by the disorder, someone must inherit an ARS mutation from both parents (autosomal recessive inheritance). Someone who only inherits an ARS mutation from a single parent is called a carrier, and they usually do not have any medical symptoms. If both parents are carriers, there is a 1 in 4 chance with each pregnancy that their child will have mtARS. Both males and females can have mtARS.

There are many Mitochondrial ARS genes, and all are named with an -ARS2 naming system with the exception of GARS and KARS:

Gene Protein Main Phenotype
AARS2 Mt alanyl-tRNA synthetase Progressive leukoencephalopathy with Ovarian Failure (LKENP); Cardiomyopathy – Combined Oxidative phosphorylation defect type 8 (COXPD8)
CARS2 Mt cysteinyl-tRNA synthetase Mitochondrial epileptic encephalopathy – Combined oxidative phosphorylation defect type 27 (COXPD27)
DARS2 Mt aspartyl-tRNA synthetase Leukoencephalopathy with brain stem and spinal cord involvement – high lactate syndrome (LBSL)
EARS2 Mt glutamyl-tRNA synthetase Leukoencephalopathy with thalamus and brainstem involvement and high lactate elevation (LTBL) – Combined oxidative phosphorylation defect type 12 (COXPD12)
FARS2 Mt phenylalanyl-tRNA synthetase Spastic paraplegia 77 (SPG77); Infantile onset epilepsy and encephalopathy – Combined oxidative phosphorylation deficiency-14 (COXPD14)
GARS Mt and cyt glycyl-tRNA synthetase Systemic mitochondrial disease cardiomyopathy; Autosomal dominant Charcot-Marie Tooth disease type 2D Distal hereditary motor neuropathy type 5
HARS2 Mt histidyl-tRNA synthetase Perrault syndrome 2
IARS2 Mt isoleucyl-tRNA synthetase Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (CAGSSS)
KARS Mt and cyt lysyl-tRNA synthetase Charcot-Marie-Tooth disease, recessive intermediate, B; Deafness, autosomal recessive 89; Deafness, congential, and adult-onset leukoencephalopathy; Leukoencephalopathy, progressive, infantile onset, with or without deafness
LARS2 Mt leucyl-tRNA synthetase Perrault syndrome 4 ; Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
MARS2 Mt methionlyl-tRNA synthetase Autosomal recessive spastic ataxia with leukoencephalopathy; Combined oxidative phosphorylation defect type 25 (COXPD25)
NARS2 Mt asparaginyl-tRNA synthetase Deafness, autosomal recessive 94 (DFNB94); Mitochondrial DNA depletion syndrome 4A (Alpers type (MTDPS4A); Combined oxidative phosphorylation deficiency 24 (COXPD24)
PARS2 Mt prolyl-tRNA synthetase Developmental and epileptic encephalopathy 75 (DEE75)
QARS Mt and cyt glutaminyl-tRNA synthetase 1 Microcephaly, progressive, with seizures and cerebral and cerebellar atrophy (MSCCA)
RARS2 Mt arginyl-tRNA synthetase Pontocerebellar hypoplasia type 6 (PCH6)
SARS2 Mt seryl-tRNA synthetase Progressive spastic paresis; Hyperuricemia – pulmonary hypertension – renal failure – alkalosis syndrome (HUPRA syndrome)
TARS2 Mt threonyl-tRNA synthetase Combined oxidative phosphorylation deficeincy-21 (COXPD21)
VARS2 Mt valyl-tRNA synthetase Combined oxidative phosphorylation deficeincy-20 (COXPD20)
WARS2 Mt tryptophanyl-tRNA synthetase Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizure; Parkinsonism-dystonia 3, childhood onset
YARS2 Mt tyrosyl-tRNA synthetase Mitochondrial myopathy and sideroblastic anemia (MLASA)

Signs and Symptoms of mtARS: Mitochondrial Aminoacyl-tRNA Synthetase Disorders

All Mitochondrial ARS Disorders affect the brain and may also affect other high energy systems. All ARS2 genes are progressive and neurodegenerative. mtARS can develop at any age, but it most often develops in children. Signs and symptoms of mtARS can include:

  • Developmental Delays
  • Ataxia (imbalance)
  • Hypotonia (low muscle tone)
  • Poor growth/failure to thrive
  • Tremors
  • Seizures
  • Hearing or Vision Loss
  • Issues with eye movement
  • Gastrointestinal dysmotility/Constipation
  • Swallowing issues/Feeding Tube
  • Dementia
  • Heart issues
  • High Lactic Acid
  • Neuropathy (tingling, weakness, or pain – commonly in the hands and feet – caused by damage to nerves leading to the brain)
  • Dysautonomia (malfunction of autonomic nervous system, which regulates heart rate, blood pressure, temperature control and more).
  • Parkinsonism (movement symptoms): slowed movements, balance issues, stiffness and tremors.
  • Issues in any high energy organs, such as the heart, kidney, liver, or digestive tract.

Several of the ARS genes cause a white matter brain disease, also known as a leukodystrophy. Due to lack of energy in the brain cells, the cells in the white matter can begin to die. Other genes may effect the brain as a whole, known as an encephalopathy.

Resources

Connecting with others impacted by a rare disease allows for vital information to be shared about day-to-day life, prevents isolation, and gives hope. Please contact MitoAction for peer support opportunities at 888-MITO-411 or email mito411@mitoaction.org.

Other resources we recommend are:

  • New Patient Kit for Mitochondrial Conditions
  • Planning and Preparation
  • Monthly Expert Series
  • Energy in Action Podcast

MitoAction does not provide medical advice, diagnosis, treatment, or legal advice. It is essential that all those living with or caring for someone with a Mitochondrial or FAOD disease have an emergency protocol letter. These letters, which are written and signed by a doctor, share details about prescribed treatment during crises and in emergency room settings. Always check with your doctor if you or your child has concerns as everyone may present with symptoms differently. Before beginning any treatment or therapy, please consult with your physician.

Sources:

  • CureARS https://www.curears.org/ars-genes

Last Updated: 11/15/2024

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